TY - JOUR
T1 - In vitro studies into establishing therapeutic bioequivalence of complex topical products
T2 - Weight of evidence
AU - Miranda, Margarida
AU - Volmer, Zoe
AU - Cornick, Alicia
AU - Goody, Aidan
AU - Cardoso, Catarina
AU - Pais, Alberto A.C.C.
AU - Brown, Marc
AU - Vitorino, Carla
N1 - Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2024/5/10
Y1 - 2024/5/10
N2 - Over the past decade, topically applied drug products have experienced extraordinary price increases, due to the shortage of multisource generic drug products. This occurrence is mainly related to the underlying challenges evolved in topical bioequivalence documentation. Although there has been continuing regulatory efforts to present surrogate in vitro methods to clinical endpoint studies, there is still a continued need for cost- and time-efficient alternatives that account for product specificities. Hence, this work intended to expose bioequivalence assessment issues for complex topical formulations, and more specifically those related with product efficacy guidance. As a model drug and product, a bifonazole 10 mg/g cream formulation was selected and two different batches of the commercially available Reference Product (RP) were used: RP1 that displayed lower viscosity and RP4 which presented high, but not the highest, viscosity. In vitro human skin permeation testing (IVPT) was carried out and the results were evaluated by means of the traditional bioequivalence assessment approach proposed by the EMA, as well as by the Scaled Average Bioequivalence assessment approach proposed by the FDA. Based on previous experience, there was an expectation of a high level of variability in the results, thus alternative methods to evaluate local drug skin availability were developed. More specifically, an infected skin disease model, where ex vivo human skin was infected and ATP levels were used as a biological marker for monitoring antifungal activity after product application. The results showed that permeation equivalence could not be supported between the different RP batches. In contrast, this statistical difference between the formulation batches was not indicated in the disease model. Nevertheless, in pivotal IVPT studies, the lowest permeant formulation (RP4) evidenced a higher antifungal in vitro activity as reported by the lower levels of ATP. A critical appraisal of the results is likewise presented, focusing on an outlook of the real applicability of the regulatory guidances on this subject.
AB - Over the past decade, topically applied drug products have experienced extraordinary price increases, due to the shortage of multisource generic drug products. This occurrence is mainly related to the underlying challenges evolved in topical bioequivalence documentation. Although there has been continuing regulatory efforts to present surrogate in vitro methods to clinical endpoint studies, there is still a continued need for cost- and time-efficient alternatives that account for product specificities. Hence, this work intended to expose bioequivalence assessment issues for complex topical formulations, and more specifically those related with product efficacy guidance. As a model drug and product, a bifonazole 10 mg/g cream formulation was selected and two different batches of the commercially available Reference Product (RP) were used: RP1 that displayed lower viscosity and RP4 which presented high, but not the highest, viscosity. In vitro human skin permeation testing (IVPT) was carried out and the results were evaluated by means of the traditional bioequivalence assessment approach proposed by the EMA, as well as by the Scaled Average Bioequivalence assessment approach proposed by the FDA. Based on previous experience, there was an expectation of a high level of variability in the results, thus alternative methods to evaluate local drug skin availability were developed. More specifically, an infected skin disease model, where ex vivo human skin was infected and ATP levels were used as a biological marker for monitoring antifungal activity after product application. The results showed that permeation equivalence could not be supported between the different RP batches. In contrast, this statistical difference between the formulation batches was not indicated in the disease model. Nevertheless, in pivotal IVPT studies, the lowest permeant formulation (RP4) evidenced a higher antifungal in vitro activity as reported by the lower levels of ATP. A critical appraisal of the results is likewise presented, focusing on an outlook of the real applicability of the regulatory guidances on this subject.
KW - Antifungals
KW - Disease model
KW - IVPT
KW - Regulatory science
KW - Topical bioequivalence
KW - Viscosity
KW - Skin/metabolism
KW - Humans
KW - Skin Absorption
KW - Skin Cream/pharmacokinetics
KW - Administration, Cutaneous
KW - Antifungal Agents/pharmacokinetics
KW - In Vitro Techniques
KW - Therapeutic Equivalency
UR - http://www.scopus.com/inward/record.url?scp=85190103645&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2024.124012
DO - 10.1016/j.ijpharm.2024.124012
M3 - Article
C2 - 38537923
AN - SCOPUS:85190103645
SN - 0378-5173
VL - 656
SP - 124012
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
M1 - 124012
ER -